Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway

Stefan Peukert; Rishi K Jain; Adrian Geisser; Yingchuan Sun; Rui Zhang; Aaron Bourret; Adam Carlson; Jennifer Dasilva; Arun Ramamurthy; Joseph F Kelleher

doi:10.1016/j.bmcl.2008.11.096

Identification and structure-activity relationships of ortho-biphenyl carboxamides as potent Smoothened antagonists inhibiting the Hedgehog signaling pathway

Bioorg Med Chem Lett. 2009 Jan 15;19(2):328-31. doi: 10.1016/j.bmcl.2008.11.096. Epub 2008 Dec 3.

Authors

Stefan Peukert¹, Rishi K Jain, Adrian Geisser, Yingchuan Sun, Rui Zhang, Aaron Bourret, Adam Carlson, Jennifer Dasilva, Arun Ramamurthy, Joseph F Kelleher

Affiliation

¹ Novartis Institutes for BioMedical Research, Inc., 250 Massachusetts Avenue, Cambridge, MA 02139, USA. [email protected]

PMID: 19091559
DOI: 10.1016/j.bmcl.2008.11.096

Abstract

Ortho-biphenyl carboxamides, originally prepared as inhibitors of microsomal triglyceride transfer protein (MTP) have been identified as novel inhibitors of the Hedgehog signaling pathway. Structure-activity relationship studies for this class of compounds reduced MTP inhibitory activity and led to low nanomolar Hedgehog inhibitors. Binding assays revealed that the compounds act as antagonists of Smoothened and show cross-reactivity for both the human and mouse receptor.

MeSH terms

Amides / chemistry
Amides / pharmacology*
Animals
Carrier Proteins / antagonists & inhibitors
Hedgehog Proteins / antagonists & inhibitors*
Hedgehog Proteins / metabolism
Humans
Mice
Receptors, G-Protein-Coupled / antagonists & inhibitors*
Signal Transduction / drug effects*
Smoothened Receptor
Structure-Activity Relationship

Substances

Amides
Carrier Proteins
Hedgehog Proteins
Receptors, G-Protein-Coupled
SMO protein, human
Smo protein, mouse
Smoothened Receptor
microsomal triglyceride transfer protein